D-erythro-2,2-difluoro-2-deoxy-1-oxoribose is an important intermediate used in the preparation of gemcitabine of formula (A), an agent for treating non-small cell lung cancer.

Since gemcitabine is an erytliro enantiomer having the 3-hydroxy moiety oriented down (opposite to the 5-hydroxy group with respect to the place of the tetrahydrofuran ring), it is important in the preparation of gemcitabine to develop a method for preparing 1-oxoribose erythro compounds having the 3-hydroxy group oriented down.
U.S. Pat. No. 4,526,988 discloses a method for preparing an erythro 1-oxoribose compound via alkyl 2,2-difluoro-3-hydroxy-3-(2,2-dialkyldioxoran-4-yl)propionate, a 3:1 mixture of 3R-hydroxy enantiomer of formula (B) and 3S-hydroxy enantiomer of formula (B′)

wherein,
R4 and R5 are each independently C1-3 alkyl.
However, such a method involves an uneconomical step of isolating only the 3R-hydroxy enantiomer of formula (B) from the mixture of the compounds of (B) and (B′) in order to selectively prepare the desired erythro 1-oxoribose derivative, because the compounds of (B) and (B′) produce an erythro compound of formula (C) and a threo compound of formula (C′), respectively, as shown in Reaction Scheme A and B.


Further, the method also has the problem that it takes a long reaction time, almost four days at room temperature.
Meanwhile, U.S. Pat. Nos. 4,965,374; 5,223,608; and 5,434,254 disclose a method for obtaining an erythro enantiomer of formula (D), as shown in Reaction Scheme C, by (i) hydrolyzing and azeotropically distilling a 3-benzoyloxypropionate ester of formula (E) (a 3:1 mixture of 3R- and 3S-enantiomers) to obtain a lactone compound of formula (F); (ii) protecting the 5-hydroxy group of the compound of formula (F) with benzoyl to obtain a 3,5-dibenzoyloxy compound of formula (G); and (iii) cooling the compound of formula (G) to −5˜10° C. to precipitate only the erythro enantiomer of formula (D).

wherein, Bz is benzoyl.
However, the above method is uneconomical due to its overall low yield of about 25% and the use of an expensive and toxic trifluoroacetic acid in an excess amount in the hydrolyzing process.
Further, U.S. Pat. Nos. 5,428,176 and 5,618,951 teach a method of preparing a 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propionic acid ester of formula (H) having a high 3R-silylhydroxy enantiomer content by reacting a 2,2-difluoroketene silyl acetal with a glyceraldehyde derivative in a solvent such as 1,3-dimethylpropylene urea (DMPU), as shown in Reaction Scheme D.

wherein, R6 to R9 are alkyl; and R11 and R11 are C1-3 alkyl.
However, this method also requires an uneconomical column chromatography process for isolating the 3R-enantiomer from the mixture of the enantiomers.
Accordingly, the present inventors have endeavored to develop an efficient method for selectively preparing 1-oxoribose compounds having an erythro structure, and have unexpectedly found an efficient, novel method for preparing highly pure 2,2-difluoro-2-deoxy-1-oxoribose having an erytiro structure.